Growth hormone (GH), which is secreted from the pituitary gland, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic process of the body:
1. Increased rate of protein synthesis in substantially all cells of the body; PA1 2. Decreased rate of carbohydrate utilization in cells of the body; PA1 3. Increased mobilization of free fatty acids and use of fatty acids for energy. PA1 where X.sup.11 is hydrogen or optionally substituted (C.sub.1 -C.sub.6)alkyl; PA1 X.sup.12 is hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X.sup.12 is not hydrogen, X.sup.12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH.sub.3, OCH.sub.3, OCF.sub.3 and CF.sub.3 ; or X.sup.11 and X.sup.12 are taken together to form --(CH.sub.2).sub.r --L.sup.1 --(CH.sub.2).sub.r --; PA1 t is 0, 1 or 2; PA1 where X.sup.11 is hydrogen or optionally substituted (C.sub.1 -C.sub.6)alkyl; PA1 X.sup.12 is hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X.sup.12 is not hydrogen, X.sup.12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH.sub.3, OCH.sub.3, OCF.sub.3 and CF.sub.3 ; PA1 or X.sup.11 and X.sup.12 are taken together to form --(CH.sub.2).sub.r --L.sup.1 --(CH.sub.2).sub.r --; PA1 the optionally substituted (C.sub.1 -C.sub.6)alkyl defined for X.sup.11 is optionally independently substituted with phenyl, phenoxy, (C.sub.1 -C.sub.6)alkoxycarbonyl, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (C.sub.1 -C.sub.10)alkanoyloxy or 1 to 3 (C.sub.1 -C.sub.6)alkoxy; PA1 L.sup.1 is C(X.sup.2)(X.sup.2), O, S(O).sub.m or N(X.sup.2); PA1 r for each occurrence is independently 1, 2 or 3; PA1 where X.sup.11 is hydrogen or optionally substituted (C.sub.1 -C.sub.6)alkyl; PA1 X.sup.12 is hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X.sup.12 is not hydrogen, X.sup.12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH.sub.3, OCH.sub.3, OCF.sub.3 and CF.sub.3 ; PA1 or X.sup.11 and X.sup.12 are taken together to form --(CH.sub.2).sub.r --L.sup.1 --(CH.sub.2).sub.r ; PA1 a method for increasing levels of endogenous growth hormone in a human or other animal which comprises administering to such human or other animal an effective amount of a compound of Formula I; PA1 a pharmaceutical composition useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an inert carrier and an effective amount of a compound of Formula I; PA1 a pharmaceutical composition useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an inert carrier, an effective amount of a compound of Formula I and another growth hormone secretagogue such as, GHRP-6, Hexarelin, GHRP-1, IGF-1, IGF-2, B-HT920 or growth hormone releasing factor (GRF) or an analog thereof; PA1 a method for the treatment or prevention of osteoporosis which comprises administering to a human or other animal in need of such treatment or prevention an amount of a compound of Formula 1 which is effective in treating or preventing osteoporosis; PA1 a method for the treatment or prevention of osteoporosis which comprises administering to a human or other animal with osteoporosis a combination of a bisphosphonate compound such as alendronate, and especially preferred is the bisphosphonate compound ibandronate, and a compound of Formula I; PA1 a method for the treatment or prevention of osteoporosis which comprises administering to a human or other animal with osteoporosis a combination of estrogen or Premarin.RTM. and a compound of Formula I and optionally progesterone; PA1 a method to increase IGF-1 levels in IGF-1 deficient humans or other animals which comprises administering to a human or other animal with IGF-1 deficiency a compound of Formula I; PA1 a method for the treatment of osteoporosis which comprises administering to a human or other animal with osteoporosis a combination of an estrogen agonist or antagonist such as tamoxifen, droloxifene, raloxifene and idoxifene and a compound of Formula I; PA1 a particularly preferred method for the treatment of osteoporosis comprises administering to a human or other animal with osteoporosis a combination of an estrogen agonist or antagonist such as Cis-6-(4fluoro-phenyl)-5-[4-(2-pipeddin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetra hydro-naphthalene-2-ol; PA1 (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro -naphthalene-2-ol; PA1 cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-nap hthalene-2-ol; PA1 cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahyd ro-naphthalene; PA1 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4-tetrah ydroisoquinoline; PA1 cis-6-(4hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetra hydro-naphthalene-2-ol; or PA1 1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-isoqu inoline and a compound of Formula I; PA1 a method for the treatment of osteoporosis which comprises administering to a human or other animal with osteoporosis a combination of calcitonin and a compound of Formula I; PA1 a method for increasing muscle mass, which method comprises administering to a human or other animal in need of such treatment an amount of a compound of Formula I which is effective in promoting release of endogenous growth hormone; and PA1 a method for promoting growth in growth hormone deficient children which comprises administering to a growth hormone deficient child a compound of Formula I which is effective in promoting release of endogenous growth hormone. PA1 cis-6-(4-fluoro-phenyl)-5-[4-(2-pipeddin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetra hydro-naphthalene-2-ol; PA1 (-)-cis-6phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro- naphthalene-2-ol; PA1 cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-nap hthalene2-ol; PA1 cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahyd ronaphthalene; PA1 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4-tetrah ydroisoquinoline; PA1 cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetr ahydro-naphthalene-2-ol; and PA1 1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoqui noline. PA1 cis-6-(4-fluorophenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetra hydro-naphthalene-2-ol; PA1 (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro -naphthalene-2-ol; PA1 cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-nap hthalene-2-ol; PA1 cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahyd ronaphthalene; PA1 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4-tetrah ydroisoquinoline; PA1 cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetr ahydro-naphthalene-2-ol; or PA1 1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoqui noline is in the range of 0.0001 to 100-mg/kg/day, preferably 0.001 to 10 mg/kg/day.
Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in an expensive product, and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone (e.g., Jacob-Creutzfeld disease). Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic growth hormone-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.
Physiologic and pharmacologic stimulators of GH secretion include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GHRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. WO 94113696 refers to certain spiropiperidines and homologues which promote release of growth hormone. Preferred compounds are of the general structure shown below. ##STR2##
WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure ##STR3##
where L is ##STR4##
The compounds of WO 94/11012 and WO 94/13696 are reported to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.